This is a competing renewal application for continuing support for a Center of Excellence in Hematology focused on Molecular Developmental Hematopoiesis. Recent progress in the molecular dissection of blood cell development has revealed extraordinary conservation of mechanisms among vertebrate species, such that parallel study of different organisms is both complementary and synergistic for discovery. The aim of the work of this Center is the elucidation of mechanisms by which hematopoietic stem cells arise, enter the progenitor pool, and then commit to lineage differentiation. In order to achieve these goals, a program of gene discovery and functional analysis is undertaken in two genetic systems the mouse and zebrafish. Manipulation of genes in the mouse through homologous recombination offers a mean to test gene function in vivo within the intact animal throughout development. Zebrafish, a relatively recent model vertebrate organism affords the opportunity to screen for mutant phenotypes and then identify the affected genes either by positional cloning or candidate gene analysis. This Center is comprised of three COREs, whose functions complement each other. A mouse embryonic stem 9ES) cell and gene targeting core will facilitate the generation of targeted mice for members of the Center, a set of hematology and non-hematology investigators in the Harvard Medical Area and throughout Boston. A zebrafish core will maintain stocks of hematological mutants, educate and collaborate with members of the Center, and facilitate gene identification. A new core dedicated to functional genomics will provide infrastructure support for high throughput cDNA analysis, sequencing, and in situ hybridization. Its activities will complement the ES cell and zebrafish cores and lead to rapid cross-species analysis of gene function. In addition to these CORES, the Center will provide a small pilot project program and support local seminars and meetings on developmental development should provide new insights into possible approaches to stem cell expansion and management of leukemias in the future. The Center will also serve to promote interactions and collaborations in hematological research within the Boston area and in this manner move research in the field ahead and recruit new investigators to molecular hematology.